Title project: ?Unraveling the mechanisms of microhemorrhages in cerebral amyloid angiopathy; from ex vivo MRI in humans to in vivo optics in mice? Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid ? (A?) in the walls of small vessels in the brain, and is frequently observed at autopsy in the brains of Alzheimer?s disease (AD) patients. CAA manifests itself clinically by the occurrence of widespread hemorrhagic lesions, including catastrophic large hemorrhagic stroke. Moreover, CAA and CAA-related microhemorrhages - in the absence of major bleeding - have increasingly been recognized as important contributors to cognitive impairment and dementia. Finally, CAA has recently been assumed to increase the risk of developing microhemorrhages in anti-amyloid immunotherapy, which is currently the only promising treatment in patients with AD. Yet, the underlying mechanisms of hemorrhage formation are completely unknown. The proposed research responds to an urgent need to study the interaction between small vessel disease and AD, a rapidly growing research area recommended by the NIH for special emphasis. Preliminary observations suggest absence of vascular A? deposits at the sites where hemorrhages had occurred. This suggests a complex interplay between A? and vessel rupture and indicates that A? may not be directly harmful to vessels, but indirectly causes bleeding. The applicant will determine which structural and functional alterations are involved at the level of the individual vessels by combining state-of-the-art neuroimaging techniques and neuropathological examinations of human brain tissue with cutting-edge optical imaging tools in living mice. The proposal builds on the applicant?s strong background in ex vivo MRI and histopathology and her currently growing skills in multi-photon microscopy in mice. The excellent scientific environment and numerous resources provided by the Massachusetts General Hospital and Harvard Medical School, as well as the internationally recognized leadership of the applicant?s mentors, and existing collaborations with experts in the field will be key to the successful completion of the proposed research. This K99 award will be instrumental for the applicant to strengthen her skillset, further grow in her scientific and professional qualities, and take the next steps towards becoming an independent researcher. The proposed multi-modal approach will allow answering much needed questions regarding the underlying mechanisms of hemorrhage formation, with the long-term goal to find targets to prevent microhemorrhages in anti-amyloid therapies.